1. Field of the Invention
The present invention relates to a pharmaceutical composition or a health food containing a fruit extract of Lonicera caerulea L. var. edulis as an active ingredient for prevention and treatment of ischemic cerebrovascular disease.
2. Description of the Related Art
According to WHO estimates, 17 million people die of vascular disease each year, and vascular disease is the first leading cause of death, accounting for one-third of all deaths. In the U.S., vascular disease ranks as the first leading cause of death among adults aged 65 or older, and the second leading cause of death following cancer among adults aged from 45 to 64. With the growing aging population, deaths due to vascular disease are projected to increase. In South Korea, cancer is the first leading cause of death, followed by cerebrovascular disease and heart disease in that order. The number of patients with the blood circulatory diseases, being ranked as the second and third causes of death, has rabidly increased recently by 7 times, compared to the early 1980s.
Stroke is commonly known as ‘cerebrovascular accident’, and refers to a focal neurological impairment such as loss of consciousness, hemiplegia, dysarthria, which is caused by any sudden interruption in blood supply to the brain affected due to the occlusion or rupture of cerebral blood vessels. Stroke is largely divided into ischemic stroke and hemorrhagic stroke. Ischemic stroke is caused by ischemia of brain tissues due to reduction or interruption of blood supply to brain tissues, and hemorrhagic stroke is caused by bleeding in brain tissues due to a rupture of blood vessels. That is, depending on the cause, it is divided into cerebral infarction caused by blockage of cerebral blood vessel and cerebral hemorrhage caused by rupture of cerebral blood vessels, and cerebral hemorrhage is further divided into intracerebral hemorrhage and subarachnoid hemorrhage (SAH) due to rupture of cerebral aneurysm resulting from a balloon-like deformation of cerebral blood vessels. Further, cerebral infarction is divided into cerebral thrombosis (obstruction of blood vessels due to the formation of a blood clot within the cerebral blood vessels) and cerebral embolism (obstruction of a cerebral artery caused by thrombus or blood clot due to heart disorders, which was traveled to the brain). Because stroke can occur anywhere in the brain, it can cause impairments of all body functions. Further, brain injury generated is determined by severity and location of the injury itself, and severe brain injury due to stroke causes disturbances in movement and sensation, and inhibits higher functions such as memory, learning, calculation, and reasoning, etc., and also causes severe aftereffects such as stroke, weak intelligence, learning disability, epilepsy, etc. Even after stroke recovery, associated sequelae still remains in most cases, thus causing as much as 7 billion US dollars of social and economic losses each year (Davenport et al. Journal of Neurology, 2000, vol. 68, p. 277).
Ischemic brain injury depends on blood circulation. When there is a disorder in normal cerebral blood flow (50 ml/gram/minute) caused by several pathological conditions in blood vessels supplying blood to the brain, transient cerebral ischemia rapidly develops into complete stroke, leading to death. Because ischemic stroke occurs suddenly, being accompanied by neurological disorders, and progresses further within a short time, its complete treatment is impossible even with emergent thrombolytic therapy. Even if it may not lead to an immediate death, its side effects and sequelae are still so serious directly or indirectly causing social and economic losses. Accordingly, its prevention is very important.
Prevention of ischemic stroke is divided into primary prevention for removing risk factors that cause changes in blood flow such as increase in serum cholesterol level, hypertension, heart diseases, etc., and secondary prevention for preventing further aggravation after the onset of ischemic stroke. Previous studies regarding foods capable of preventing ischemic stroke have focused on reducing injuries due to particular risk factors. In particular, when brain ischemia caused by reduced blood supply to the brain occurs, the opening of calcium ion channels by glutamate leads to excessive influx of Ca ions thus causing excitotoxicity, or destroying enzyme groups in nerve cells by oxygen radicals produced via reperfusion. Target-specific studies regarding the mechanism of the neuron damage are still not satisfactory, requiring further progress in the related studies (Hagberg H et al., Neurosci Lett. 78:311-317, 1987).
In recent years, international studies have reported that food components such as carnosine, ellagic acid derivatives, carotene derivatives, S-cysteinyl derivatives influence primary and secondary prevention of ischemic brain injury. As therapeutic agents for stroke, glutamate receptor blockers for the prevention of primary (acute) brain injury, and therapeutic agent using antioxidants have been developed. However, the studies have not been successful due to lack of efficacy or toxicity problems observed during clinical trials. NMDA receptor antagonists have not been used because of severe toxicities, and most of them failed to pass clinical tests.
There have been no sufficient target-specific studies both home and abroad to elucidate the correlation between food components and the mechanisms of neuronal damage. Furthermore, there are few successful cases which have confirmed the effects of food components in animals' brains and successfully developed products therefrom. In fact, most studies in South Korea have been conducted at the level of experimental assays, and more sophisticated studies such as functional materials, mechanisms underlying in vivo physiological activities, platform technologies for modification of materials have not been well performed.
Most functional materials currently available in South Korea are simple complex type, and some of functional foods have low usefulness because of oxidation and browning due to exposure to oxygen and they also have a low-grade appearance as food materials. Thus, there is a need for the development of a basic technique capable of forming a blocking film by coating to secure storage stability and maintain activities of active ingredients, and a processing technique capable of applying active materials to proper food vehicles to improve availability. However, the efforts have not been successful yet.
To date, most drugs that have been developed as such are glutamate receptor antagonists, antioxidants, calcium or sodium ion channel blockers, etc., and effective drugs have not been developed yet. Therefore, there is a need to employ breakthrough ideas and a new concept for the accomplishment of target-specific drug discovery.
Meanwhile, reportedly, inflammatory reactions occur in the central nervous system, thus becoming one of the major causes of neuronal degeneration. Thus, the inflammatory reactions appearing after the occurrence of the brain ischemic stroke will become a target for the development of a novel therapeutic agent for stroke. Such therapeutic agent are expected to be comprised of the medicines either to suppress the enzyme activity involved in the separation of cytotoxic substances or to suppress the deposition of neutrophils (Dirnagl, U. et al; TINS., 22, pp 391-397, 1999).
Hewett et al. discovered that activated glial cells may affect death of nerve cells (Hewett, S. J. et al: Neuron, 13:487-494 1994; Hewett, S. J. et al, Stroke, 27:1586-15911996). Activated glial cells increase production of inflammatory factor, cytokine such as TNF-alpha, interleukin which can cause cytotoxicity, thereby increasing cytotoxicity on nerve cells and glial cells.
Inflammatory molecules secreted from macrophage and microglia, and death of nerve cells thereby are important, and in particular, control of glial cell activation and protection of nerve cells are the main targets for the prevention and control of stroke and development of therapy.
The efforts to develop novel crops for a special purpose using plants have enabled their annual production increase, but their utilization has been low for being used as general additives through a simple process such as an oil extraction process, or added to oriental medicines in the form of extracts. However, because plants are highly expected to contain active substances showing prophylactic activity against ischemic stroke, and several plants have been traditionally used for the prevention of stroke in the oriental medicine, development of plants as health food materials is expected to render an added value on the plants. Accordingly, there is a need for a systematic approach to develop functional health foods by developing a technology capable of screening food materials for preventing ischemic stroke from domestic plants, investigating their efficacy in animal tests, and then applying them to functional foods.
Lonicera caerulea L. var. edulis is a dicotyledonous plant belonging to the Family Caprifoliaceae of the Order Rubiales. It is a deciduous shrub growing to 1.5 m in height, densely branched, and has shield-shaped bracts at nodes of twigs. The inner part of branches is white. The leaves are opposite, lanciform or elliptic and blunt- or sharp-ended, lack teeth on the margins, have short hairs on the margins and surface, and have many wooly hairs underneath. The flowers usually have short stalks, which arise from leaf axils, have funnel-shaped creamy white corollas, and bloom in summer. Each calyx has five toothed sepals. The corollas are yellowish white, cylindrical campanulate, 1.2-1.5 cm long, and slightly hairy. The stamens are shorter than styles and have no hairs, and the two ovaries are fused together. The fruits are oval or nearly circular, ripen to purplish black between July and October, and are covered with white powder. This shrub is an arctic plant that is widespread in Siberia, Sakhalin, the Northern region of China, Tibet, North Korea, and the like.
At present, as the inventions regarding the use of Lonicera caerulea L. var. edulis extract, Korean Patent No. 10-0699790 discloses a pharmaceutical composition containing Lonicera caerulea L. var. edulis extract for the prevention and treatment of liver disease, in which the composition exhibits prophylactic and therapeutic effects on liver cancer, hepatocirrhosis, and fatty liver, and Korean Patent No. 10-0454150 discloses an anti-irritant cosmetic composition including 0.001˜10% by weight of one or more herbal extracts selected from the group consisting of Corydalis turtschaminovii, Cynanchum paniculatum, and Lonicera caerulea L. var. edulis, based on the total weight of the composition, in which it can be used for the prevention of itching with fewer side effects such as skin rash or skin allergy. However, there have been no inventions regarding the use of a fruit extract of Lonicera caerulea L. var. edulis in ischemic cerebrovascular disease.
Accordingly, the present inventors have explored substances that can be used for the prevention or treatment of ischaemic cerebral disease, and found that the fruit extract of Lonicera caerulea L. var. edulis inhibits neurobehavioral impairment and reduces cerebral infarct volume, and thus it can be used as an active ingredient in a prophylactic or therapeutic agent for ischaemic cerebral disease, thereby completing the present invention.